Case Report: Three pathogenic molecular findings in a patient with myotonia congenita, pseudohypoparathyroidism, and a glaucoma-suspect phenotype
TL;DR
A patient with longstanding myotonia congenita due to a CLCN1 variant in whom an incidental discovery of severe hypocalcemia led to the diagnosis of GNAS-related pseudohypoparathyroidism (PHP), demonstrating two clinically expressed Mendelian disorders together with a third actionable molecular finding.
Abstract
Background The presence of multiple rare Mendelian disorders in a single patient may mask clinical recognition when phenotypes overlap. We describe a patient with longstanding myotonia congenita due to a CLCN1 variant in whom an incidental discovery of severe hypocalcemia led to the diagnosis of GNAS-related pseudohypoparathyroidism (PHP). Exome reanalysis also identified an incidental homozygous pathogenic CYP1B1 variant associated with autosomal recessive glaucoma. Case presentation A 23-year-old man born to consanguineous parents was referred for management of chronic myotonia congenita, manifested by delayed motor milestones, frequent falls, contractures, and muscle hypertrophy. Electrophysiological assessment demonstrated myotonic discharges, and whole-exome sequencing (WES) identified a homozygous CLCN1 splice-site variant (NM_000083.3:c.1167-10T>C) known to cause myotonia congenita. During subsequent evaluation, he was found to have severe hypocalcemia, hyperphosphatemia, markedly elevated parathyroid hormone, basal ganglia and dentate calcifications, brachydactyly, subcutaneous calcifications, and mild hypothyroidism, raising suspicion for PHP. Genetic and ophthalmologic findings Reanalysis of WES data demonstrated a heterozygous frameshift GNAS variant (NM_080425.4:c.2494_2497delCTGA) and a homozygous CYP1B1 variant (NM_000104.4:c.182G>A; p.Gly61Glu) in addition to the CLCN1 defect. Sanger sequencing confirmed all three variants. The CYP1B1 finding prompted glaucoma-specialist evaluation. Visual acuity was 20/22 in the right eye and 20/25 in the left eye; intraocular pressures were 8 and 12 mmHg, respectively. The corneas were clear, cup-to-disc ratios were 0.4 and 0.5, and average retinal nerve fiber layer thicknesses were 74 and 75 µm. No definite glaucomatous damage was identified, and the patient was classified as a glaucoma suspect. After treatment with calcium, calcitriol, and ergocalciferol, serum calcium improved, parathyroid hormone levels declined, creatine kinase normalized, and the patient reported improved muscle stiffness and function. Conclusion This case demonstrates two clinically expressed Mendelian disorders together with a third actionable molecular finding. It highlights the importance of careful phenotyping, molecular testing, and cautious genotype-phenotype interpretation, particularly in consanguineous populations.